Clonal hematopoiesis of indeterminate potential in coronary disease patients: A 24-year follow-up

Abstract Background: Cardiovascular disease is highly prevalent and remains a cause of great morbi-mortality worldwide. Growing evidence suggests clonal hematopoiesis of indeterminate potential (CHIP) as an independent cardiovascular risk factor worsening overall survival (OS). However, actual data either comes from large population databases with heterogenous and/or poorly defined CVD or from smaller better-defined populations but with limited follow-up. Aims: We aimed to thoroughly characterize the extent and severity of coronary artery disease (CAD) and OS in CHIP positive patients compared to CHIP negative patients using the COROL (COROonary disease cLinico-biological determinants study) cohort which included patients undergoing coronarography and for which we now have up to 24 years of follow-up. We also evaluated long-term OS in CHIP-positive patients compared to CHIP negative patients according to their CHD status and treatment (angioplasty, medical or coronary by-pass). Methods: We retrospectively analyzed data from the 2050 COROL patients included between 2000-2001 at CHU de Lille in France. Our primary focus was CAD lesions (% of stenosis) by coronarography , treatment (medical, angioplasty or surgery), CHIP (variant allele frequency (VAF) ≥2%, determined using a 70-gene NGS panel) and OS. Statistical analysis for preliminary results included log-rank and Student analysis. The study was pproved by the ethics committe (study number: 99-345). Written consent was obtained for all patients before percuteneous coronarography. Results: Of the 1976/2050 patients that met inclusion criteria (age (mean(IQR)) : 60 years (51-70), 76,2% men), CHIP was found in 342 patients (28.5%). DNMT3a, TET2 and ASXL1 accounted for two-third of the mutated genes. Median OS was worse in both CHIP positive groups : cardiac lesions ≥ 50%, median OS in CHIP positive patients vs CHIP negative patients : 11.2 vs 14.8 years, HR : 1.32; 95% CI [1.15-1.52]; p<0.0001 and cardiac lesions < 50%, median OS in CHIP positive patients vs CHIP negative patients : 9.2 vs 18.9 years, HR : 2.06; 95% CI [1.48-2.88]; p<0.0001). Moreover, no actual CAD treatment (angioplasty, coronary by-pass or medically) could reverse the negative effect of CHIP on OS (angioplasty, median OS in CHIP positive patients vs CHIP negative patients: 12.0 vs 15.6 years HR : 1.55; 95% CI [1.28-1.87]; p<0.0001, medical, median OS in CHIP positive patients vs CHIP negative patients: 8.7 vs 13.0 years, HR: 1.62; 95% CI [0.22-2.15]; p=0.01, coronary by-pass, m edian OS in CHIP positive patients vs CHIP negative patients: 10.6 vs 12.4 years, HR: 1.59; 95% CI [0.90-3.79]; p=0.08). Conclusion: Our study is the first to provide detailed information on CAD extent and treatment in CHIP-positive patients while offering 20+ years of follow-up. It shows an independent negative effect of CHIP on OS independently of the stenosis' severity suggesting all CHIP positive patients should be followed. Moreover, actual CAD treatments do not address the negative impact of CHIP on OS. Identifying CAD patients with CHIP would be important to refine treatment in this subpopulation. Addressing inflammation is a promising avenue as it is the mechanism implicated in DNMT3A and TET2 mutations, the more frequent CHIP.